Immunologically-determined, as opposed to chemotherapy-induced, tuberculosis latency in mice requires that bacterial multiplication cease at infectious foci, and that infection become stationary under the influence of host immunity. We hypothesize that a state of latency relevant to latency in humans will not exist, however, unless stationary infection is incapable of inducing progressive pathology (disease). We hypothesize further, that this situation will exist only in mice that are genetically resistant enough to render tubercle bacilli physiologically incapable of inducing host macrophages to produce proinflammatory cytokines at sites of infection. It is proposed that these requirements for TB latency are met in all organs of genetically resistant B6 mice infected with the relatively low virulence R1Rv strain of MTB, but not with the more virulent H37Rv strain. We predict that infection with more virulent MTB strains will become stationary in all organs, and that this will result in disease latency in all organs, except the lungs. We will determine whether stationary R1Rv infection with latent disease is strikingly different from stationary H37Rv infection with progressive disease, in terms of the production in the lungs of proinflammatory and other cytokines. We will determine whether the ability of immunity to arrest disease caused by stationary infection depends on there being a certain minimal number of bacilli per lesion, depending on the virulence of the MTB strain. The relationship between latency and the expression of acquired immunity will be investigated by following the course of R1Rv infection and the development of infection-induced pathology in mice made incapable of generating one or other of T cell subpopulations that participate in protective immunity. We will determine whether already latent disease is reactivated in mice depleted of one or more of these T cell sub-populations. The need for the continuous expression of immunity to maintain latency will be investigated by monitoring Th1 and other cytokine production by T cells, as well as NOS2 expression by macrophages in organs with latent disease.